The role of reactive oxygen species in myocardial redox signaling and regulation

Abstract

Reactive oxygen species (ROS) are subcellular messengers in gene regulatory and signal transduction pathways. In pathological situations, ROS accumulate due to excessive production or insufficient degradation, leading to oxidative stress (OS). OS causes oxidation of DNA, membranes, cellular lipids, and proteins, impairing their normal function and leading ultimately to cell death. OS in the heart is increased in response to ischemia/reperfusion, hypertrophy, and heart failure. The concentration of ROS is determined by their rates of production and clearance by antioxidants. Increases in OS in heart failure are primarily a result of the functional uncoupling of the respiratory chain due to inactivation of complex I. However, increased ROS in the failing myocardium may also be caused by impaired antioxidant capacity, such as decreased activity of Cu/Zn superoxide dismutase (SOD) and catalase (CAT) or stimulation of enzymatic sources, including, cyclooxygenase, xanthine oxidase (XO), nitric oxide synthase, and nonphagocytic NAD(P)H oxidases (Noxs). Mitochondria are the main source of ROS during heart failure and aging. Increased production of ROS in the failing heart leads to mitochondrial permeability transition, which results in matrix swelling, outer membrane rupture, a release of apoptotic signaling molecules, and irreversible injury to the mitochondria. Alterations of “redox homeostasis” leads to major cellular consequences, and cellular survival requires an optimal regulation of the redox balance.